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Title: Structural basis for human PRDM9 action at recombination hot spots

Journal Article · · Genes & Development
 [1];  [1];  [2];  [1];  [1]
  1. Emory Univ. School of Medicine, Atlanta, GA (United States)
  2. New England Biolabs, Ipswich, MA (United States)
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The multidomain zinc finger (ZnF) protein PRDM9 (PRD1–BF1–RIZ1 homologous domain-containing 9) is thought to influence the locations of recombination hot spots during meiosis by sequence-specific DNA binding and trimethylation of histone H3 Lys4. The most common variant of human PRDM9, allele A (hPRDM9A), recognizes the consensus sequence 5'-NCCNCCNTNNCCNCN-3'. We cocrystallized ZnF8–12 of hPRDM9A with an oligonucleotide representing a known hot spot sequence and report the structure here. ZnF12 was not visible, but ZnF8–11, like other ZnF arrays, follows the right-handed twist of the DNA, with the α helices occupying the major groove. Each α helix makes hydrogen-bond (H-bond) contacts with up to four adjacent bases, most of which are purines of the complementary DNA strand. The consensus C:G base pairs H-bond with conserved His or Arg residues in ZnF8, ZnF9, and ZnF11, and the consensus T:A base pair H-bonds with an Asn that replaces His in ZnF10. Most of the variable base pairs (N) also engage in H bonds with the protein. These interactions appear to compensate to some extent for changes from the consensus sequence, implying an adaptability of PRDM9 to sequence variations. We investigated the binding of various alleles of hPRDM9 to different hot spot sequences. Allele C was found to bind a C-specific hot spot with higher affinity than allele A bound A-specific hot spots, perhaps explaining why the former is dominant in A/C heterozygotes. Allele L13 displayed higher affinity for several A-specific sequences, allele L9/L24 displayed lower affinity, and allele L20 displayed an altered sequence preference. These differences can be rationalized structurally and might contribute to the variation observed in the locations and activities of meiotic recombination hot spots.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH)
Grant/Contract Number:
GM049245-22
OSTI ID:
1237740
Journal Information:
Genes & Development, Vol. 30, Issue 3; ISSN 0890-9369
Publisher:
Cold Springs Harbor Laboratory PressCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 37 works
Citation information provided by
Web of Science

References (36)

PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots journal September 2015
PRDM9 Is a Major Determinant of Meiotic Recombination Hotspots in Humans and Mice journal December 2009
PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans journal September 2010
Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations journal July 2011
Genetic recombination is directed away from functional genomic elements in mice journal May 2012
Structure of PvuII endonuclease with cognate DNA. journal September 1994
Coot model-building tools for molecular graphics journal November 2004
Competition Between Adjacent Meiotic Recombination Hotspots in the Yeast Saccharomyces cerevisiae journal March 1997
High Diversity at PRDM9 in Chimpanzees and Bonobos journal July 2012
An improved predictive recognition model for Cys2-His2 zinc finger proteins journal February 2014
A histone H3 methyltransferase controls epigenetic events required for meiotic prophase journal November 2005
The landscape of recombination in African Americans journal July 2011
Carbon-Oxygen Hydrogen Bonding in Biological Structure and Function journal October 2012
Human recombination hot spots hidden in regions of strong marker association journal May 2005
Recombination regulator PRDM9 influences the instability of its own coding sequence in humans journal December 2012
Refinement of Eco RI endonuclease crystal structure: a revised protein chain tracing journal September 1990
The Discovery of Zinc Fingers and Their Applications in Gene Regulation and Genome Manipulation journal June 2010
Fine-scale recombination rate differences between sexes, populations and individuals journal October 2010
Amino acid-base interactions: a three-dimensional analysis of protein-DNA interactions at an atomic level journal July 2001
A Fine-Scale Map of Recombination Rates and Hotspots Across the Human Genome journal October 2005
A common sequence motif associated with recombination hot spots and genome instability in humans journal August 2008
Single nucleotide polymorphisms and recombination rate in humans journal September 2001
Polymorphism in the activity of human crossover hotspots independent of local DNA sequence variation journal March 2006
Accelerated Evolution of the Prdm9 Speciation Gene across Diverse Metazoan Taxa journal December 2009
Multiparametric scaling of diffraction intensities journal April 2003
De novo prediction of DNA-binding specificities for Cys2His2 zinc finger proteins journal October 2013
Recombination initiation maps of individual human genomes journal November 2014
A New Generation of Crystallographic Validation Tools for the Protein Data Bank journal October 2011
The Case of the Fickle Fingers: How the PRDM9 Zinc Finger Protein Specifies Meiotic Recombination Hotspots in Humans journal December 2011
Extraordinary Molecular Evolution in the PRDM9 Fertility Gene journal December 2009
High-Resolution Recombination Patterns in a Region of Human Chromosome 21 Measured by Sperm Typing journal May 2006
A view of consecutive binding events from structures of tetrameric endonuclease Sfi I bound to DNA : The structure of journal November 2005
The crystal structure of EcoRV endonuclease and of its complexes with cognate and non-cognate DNA fragments. journal May 1993
DNA Recognition by Cys 2 His 2 Zinc Finger Proteins journal June 2000
Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9 journal October 2013

Cited By (24)

Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G-quadruplex forming sequences journal July 2018
Structural basis for histone H3K4me3 recognition by the N-terminal domain of the PHD finger protein Spp1 journal July 2019
Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice posted_content April 2017
Methyl-dependent and spatial-specific DNA recognition by the orthologous transcription factors human AP-1 and Epstein-Barr virus Zta journal February 2017
EWSR1 affects PRDM9-dependent histone 3 methylation and provides a link between recombination hotspots and the chromosome axis posted_content March 2018
TvZNF1 is a C2H2 zinc finger protein of Trichomonas vaginalis journal October 2017
The consequences of sequence erosion in the evolution of recombination hotspots
  • Tiemann-Boege, Irene; Schwarz, Theresa; Striedner, Yasmin
  • Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 372, Issue 1736 https://doi.org/10.1098/rstb.2016.0462
journal November 2017
PRDM9 forms a trimer by interactions within the zinc finger array journal July 2019
Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice journal September 2017
The cell cycle-regulated DNA adenine methyltransferase CcrM opens a bubble at its DNA recognition site journal October 2019
PRDM9, a driver of the genetic map journal August 2018
The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification journal August 2019
Regulatory remodeling in the allo-tetraploid frog Xenopus laevis journal March 2017
Structure of HhaI endonuclease with cognate DNA at an atomic resolution of 1.0 Å journal December 2019
Ruminant-specific multiple duplication events of PRDM9 before speciation journal March 2017
The long zinc finger domain of PRDM9 forms a highly stable and long-lived complex with its DNA recognition sequence journal February 2017
DUF3669, a “domain of unknown function” within ZNF746 and ZNF777, oligomerizes and contributes to transcriptional repression journal December 2019
Role for first zinc finger of WT1 in DNA sequence specificity: Denys–Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites journal December 2017
Interrogating the Functions of PRDM9 Domains in Meiosis journal April 2018
The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification. text January 2019
Regulatory remodeling in the allo-tetraploid frog Xenopus laevis journal October 2017
The histone codes for meiosis journal September 2017
A placental growth factor is silenced in mouse embryos by the zinc finger protein ZFP568 journal May 2017
Ruminant-specific multiple duplication events of PRDM9 before speciation text January 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
PRDM9
crystallography
recombination hot spots
zinc finger arrays